Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1...

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Frontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials Howard Rosen, M.D. UCSF Department of Neurology Memory and Aging Center www.memory.ucsf.edu

Transcript of Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1...

Page 1: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Frontotemporal

lobar degeneration

Clinical Approaches and

Preparation for Clinical Trials

Howard Rosen, M.D.

UCSF Department of Neurology

Memory and Aging Center

www.memory.ucsf.edu

Page 2: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

51 year old man with four

years of personality change

Page 3: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Disclosures

• Consultant

– Ionis pharmaceuticals

– Wave neuroscience

• Investigator

– Biogen pharmaceuticals

• Feel like a consultant for Mars, Heshey’s Inc.

Page 4: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Frontotemporal dementia

Behavioral variant of frontotemporal

dementia (bvFTD)

• Clinical Features

– Disinhibition/antisocial behavior

– Loss of concern for others

– Exceedingly poor judgment

– Overeating

– Compulsive behaviors (collecting)

– Loss of executive control

– Apathy

Page 5: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Overview

• Brief review of FTLD

– Clinical

– Pathological

– Genetic

• Ongoing studies to prepare for clinical trials

– ALLFTD

Page 6: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Frontotemporal lobar degeneration (FTLD)

• Group of disorders

– Overarching term

• Original term

– Neary et al, 1998

– Circumscribed progressive deterioration of the frontal and/or temporal lobes

– Three clinical syndromes

Page 7: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

3 traditional clinical variants of FTLD

Behavioral variant Language variants

Semantic

variantNonfluent variant

R L

R L R L

Also:

“Frontal variant” FTD

“FTD”

Page 8: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Orbitofrontal cortex (inhibition)

Anterior cingulate cortex (drive)Dorsolateral PFC

(Executive control)

Page 9: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Traditional Frontal

Neuropsychology:

Mostly dorsolateral frontal

• Working memory (BA46) – digit back

• Generation – letters, animals, shapes

• Inhibition – Stroop, antisaccade, flanker task

• Alternate sequence – dorsolateral – Trails B

• Combination – Card sorts

• Abstraction – proverbs

Page 10: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

The frontal lobes are important for

regulation of social behavior

Phineas Gage, 1823 - 1860

Page 11: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

…because his personality had changed so much, the contractors

who had employed him would not give him his place again. Before

the accident he had been their most capable and efficient foreman,

one with a well-balanced mind, and who was looked on as a

shrewd smart business man. He was now fitful, irreverent, and

grossly profane, showing little deference for his fellows. He was

also impatient and obstinate, yet capricious and vacillating, unable

to settle on any of the plans he devised for future action. His

friends said he was “No longer Gage.”

Gage had a dramatic change in

personality after the accident

Page 12: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Right

Hemisphere

Left

HemisphereBottom

Mid-Sagittal

SectionFTD

vs.

Controls

AD

vs.

Controls•t

•max

•min

FTD is associated with bizarre socioemotional changes

because of its specific neuroanatomy

Regions of gray matter atrophy in FTD and AD

•p<0.05, corrected for multiple comparisons

Page 13: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

3 traditional clinical variants of FTLD

Behavioral variant Language variants

Semantic

variantNonfluent variant

R L

R L R L

Also:

“Frontal variant” FTD

“FTD”

Page 14: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

• Profound anomia

• Problems with word comprehension

• Fluent, empty speech

• Trouble with object recognition (agnosia)

• Trouble with recognition of familiar/famous faces

Semantic variant of Primary

Progressive Aphasia (svPPA)

Page 15: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

svPPA

Page 16: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

3 traditional clinical variants of FTLD

Behavioral variant Language variants

Semantic

variantNonfluent variant

R L

R L R L

Also:

“Frontal variant” FTD

“FTD”

Page 17: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

• Hesitant, non-fluent, Broca-like speech

• Agrammatism

− Decreased use of function words

− Sometimes “telegraphic” speech

• Articulation difficulties

− Difficulty with individual words

− Speech apraxia

Nonfluent variant of Primary

Progressive Aphasia (nfvPPA)

Page 18: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

nfvPPA

Page 19: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Common feature across these syndromes is

pathology• Nomenclature

– Frontotemporal lobar degeneration (FTLD)

• Two main pathologies (intracellular inclusions)

– Tau – ~ 48%

– TDP-43 – ~50%

– Fused in sarcoma (FUS) – ~2%

• Other disorders previously not linked to FTLD have same pathology

– Tau

• Movement disorders (Parkinson’s plus)

– Progressive supranuclear palsy (PSP)

– Cortibobasal degeneration (CBD)

• Chronic Traumatic Encephalopathy (CTE)

• Argyrophilic grain disease (AGD)

– Tar DNA binding protein 43 (TDP-43) pathology

• Amyotrophic lateral sclerosis

Page 20: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Etiology of FTLD is unknown

• ~ 70% sporadic (sFTLD)

• ~ 30% familial (fFTLD)

– family history suggesting autosomal dominant inheritance

• Multiple mutations have been identified

– Chromosome 9 open reading frame 72 (C9orf72) – 25%

– Progranulin protein (GRN) – 5-20%

– Microtubule associated protein tau (MAPT) – 10-20% – <2%

– Valosin Containing Protein (VCP) – <2%

– Charged multivesicular body protein 2B (CHMP-2B) – <2%

– Tar DNA binding protein 43 (TDP-43) – <2%

– Fused in Sarcoma (FUS) – <2%

– Tank Binding Kinease 1 (TBK1) – <2%

• Likely more to be discovered

– ? 50% of familial cases without identified mutation

Page 21: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Variable links between clinical features and

pathology

• Tau

– (Almost) Always tau

• PSP

• MAPT mutations

• CTE*

• Pick’s disease*

– Commonly tau (more than 50%)

• CBD

– Sometimes tau

• bvFTD (50%)

• nfvPPA (50%)

* Pathologically defined disease, specific clinical features not established

• TDP-43

– (Almost) Always TDP

• ALS

• svPPA

• GRN mutations

• C9orf72

– Sometimes TDP

• bvFTD (50%)

• nfvPPA (50%)

• Mutation-clinical

– C9orf72

• ALS

• bvFTD common

• Any of other syndromes

– GRN

• Language disorders common

• Any syndrome other than ALS

– MAPT

• Any syndrome other than ALS

– svPPA rare in any mutation

Page 22: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

FTLD is not uncommon

• Common cause pre-senile dementia

– 1:1 with AD 45-64 years (Ratnavalli, Hodges 2002)

– More common than AD below 60 yrs (Knopman 2004)

• Rare after 70?

– 3% clinical prevalence of FTD 80-90 (2003 Skoog)

– Include diseases with similar molecules: PSP, CBD, ALS even more common

– Association TDP-43 & cognition independent of plaque, hippocampal sclerosis (Nelson 2008)

– Tau and TDP-43 major proteins in “chronic traumatic encephalopathy” NFL football players’ dementia (also found following war trauma)

Page 23: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

New mechanisms in FTLD: development

Increased likelihood of left-handedness in svPPA

(and lvPPA)

Page 24: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

New mechanisms in FTLD: development

• Nearly 1 in 5 FTD STEM occupation

• STEM careers in FTD are nearly 3x that of AD & PSP and population estimates (p<0.001)

Association between FTLD and STEM professions

Page 25: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

• Autoimmune diseases 3x more likely in TDP-43 FTLD than expected– Inc TNF-alpha in

svPPA and GRN

Z Miller et al, JNNP, 2013

New mechanisms in FTLD: immune

activation

Page 26: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

FTLD and immune diseases

share genetic risk in HLA regions

Broce et al, PLoS Medicine, 2018

Page 27: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Misdiagnosis of FTLD: Alzheimer’s disease

• Executive function Frontal disorder FTD

– Disorganization

– Distraction

– Poor planning

– Poor performance on cog testing (executive fxn)

• Progressive aphasia FTLD

– lvPPA

Page 28: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Logopenic variant of primary

progressive aphasia (lvPPA)

• Hesitant, nonfluent speech

– Particularly due to word finding

• Islands of preserved speech/phrases

• Relatively good articulation

• Relatively poor comprehension

• Pathology is usually Alzheimer’s disease

Page 29: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

lpvPPA

Page 30: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

0

10

20

30

40

50

60

70

bvFTD(n=69)

AD (n=65) svPPA(n=41)

nfvPPA(n=17)

CBD(n=25)

PSP(n=15)

ALS(n=20)

Men

Women

Total

Rates Psychiatric Diagnosis within each

Neurodegenerative Disease

Woolley et al. J Clin Psychiatry 2011

•Pe

rce

nt o

f S

am

ple

Misdiagnosis of FTLD: psychiatric illness

Page 31: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Regions of Atrophy in FTD (Rosen et al, Neurology, 2002)

Regions atrophy Bipolar disorder (meta-analysis Bora et al, Biol Psych, 2010)

Page 32: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Diagnosis if primarily clinical

• Sensitivity and specificity above 80%

– Autopsy-confirmed cases

Page 33: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

AD

FTLD

CONT

DVR

0

2.5

Biomarkers in diagnosis: Amyloid Imaging

Rabinovici et al, Neurology, 2007

Rabinovici et al, Neurology, 2011

• Differentiate AD vs FTLD

• Not helpful for:

– FTLD protein prediction

– Early diagnosis/prediction

Page 34: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Plasma measures of AD-related proteins are

on the horizon (currently experimental)

Ovod et al, Alz & Dem 2017

Plasma abeta-42 Plasma p-tau

Thijssen et al, submitted, courtesy of Adam Boxer

Page 35: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Neurofilament light chain (NfL):

a marker of neuronal injury

• Several diseases– Multiple sclerosis

– Traumatic brain injury

– Amyotrophic lat sclerosis

– HIV

Scherling et al, Ann Neurol 2014

Elevated in FTLD

Correlates with degree of brain atrophy

Plasma and CSF levels correlate

Rojas et al, Ann Clin Trans Neurol 2016

Page 36: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Al Shweiki et al, Jo Psych Res, In press

NfL separates bvFTD from psychiatric

disorders

Page 37: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Symptoms of FTLD represent end of a

long process

Risk/

Mutation

Bio-

chemical

Changes

Early

pathological

changes

Neural

systems

Dysfunction

Presymptomatic Carriers

Non-carriers

Symptomatic CarriersDetectable change

in cog/behavioral

function

Presymptomatic Symptomatic

Page 38: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Familial FTLD (fFTLD) is becoming an

important focus for studies of FTLD

• Recruit participants before symptoms develop–Identify predictive markers

–Prepare for studies of prevention

• Specific/predictable mechanisms–Related to each mutation

Page 39: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

New studies are addressing the full

spectrum of FTLD

• ARTFL-LEFFTDS Longitudinal FTLD (ALLFTD)– 19 sites

– Familial FTLD• >650 participants (symptomatic,

asymptomatic)

– Sporadic FTLD• >750 cases

Page 40: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Individualized atrophy maps (w-score)

Supervised classification algorithm (logistic regression)

Imaging based dementia classification

Imaging-based dementia prediction score

Prospective prediction of conversion to dementia

Baseline atrophy predicts risk of

conversion to dementia

Page 41: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Non-carriers C9orf72 GRN MAPT

MBI = mild behavioral impairment

MCI = mild cognitive impairment

Confidential—not for distributionRojas et al., in revision

NfL is also elevated in fFTLD

Page 42: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

NfL also predicts higher rate of

decline in fFTLD

Rojas et al, submitted

Page 43: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

•H.P.I. (sister)

• Symptomatic management

• SSRIs (e.g. citalopram)

• Trazadone

• Atypical antipsychotics

• AVOID cholinesterase inhibitors in bvFTD

• May exacerbate symptoms/increase agitation

• Specific treatment

• Trial of memantine failed

• Speech therapy for language disorders

• Under investigation

Current treatment of FTLD

Page 44: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Table 1. Potential FTLD Therapeutics

Drug Mode of Action Status

GRN-targeted therapeutics

FRM-0334 HDAC inhibitor Phase 2 (negative)

Chloroquine Vesicular pH modulator Repurposed

Nimodipine Increased progranulin secretion Repurposed; phase 1b (neg)

AL-001 Anti-sortilin mAb Phase 1

Proprietary A, B HDAC inhibitor Preclinical

Proprietary A-C AAV gene therapy Preclinical

C9orf72 therapeutics:

Proprietary A, B C9orf72 antisense oligos Phase 1 ALS; FTLD planned

Tau-targeted therapeutics:

LMTX (Methylene Blue) Protein clearance activator Phase 3 (neg. for bvFTD)

Lithium carbonate GSK inhibitor Phase 2 FTD

Abeotaxane (TPI-287) microtubule stabilizer Phase I (neg. for CBD, PSP)

Salsalate Tau acetylation inhibitor Phase 1 PSP; abandoned

ABV-8E12 N-terminal anti-tau mAb Phase 2 PSP

BIIB092 N-terminal anti-tau mAb Phase 2 PSP

BIIB092 N-terminal anti-tau mAb Phase 1b: CBD, nfvPPA, sMAPT

AADvac1 Active anti-tau vaccine Phase 1: nfvPPA

UCB0107 Mid-domain anti-tau mAb Phase 1

ASN001 o-GlcNACase inhibitor Phase 1

IONIS-MAPTrx Antisense oligonucleotide Phase 1 ADOther (Immunomodulatory, neuroprotective therapeutics):

NP001 Macrophage activation inhibitor Phase 2 ALS negative

DLZ Kinase inhibitor Neuroprotective agent Phase 1 ALSPalliative Approaches:

Oxytocin Symptomatic improvement Phase 2 bvFTD

Rivastigmine Cholinesterase inhibitor Phase 2 PSP

Transcranial DC stim Electric current stimulation N/A (pilot) bvFTD, PPA

Transcranial magn. stim Magnetic field stimulation PPA

Variety of treatments being investigated

Boxer et al, Alz & Dem, in press

Page 45: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Antisense oligonucleotides (ASO’s) are a

powerful new form of treatment

• Pipelines targeted at: – Cardiac disorders/HTN

– Metabolic/renal disorders

– Cancer

– Infectious diseases

– Rare inherited disorder

– Neurological disorders

Page 46: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

ASO’s reduce expression of tau

Reduced human tau mRNA, reduced tau deposition, hippocampal volume loss and increased survival, nesting behavior.

DeVos et al 2017

Page 47: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

ASO’s provided the first disease modifying

treatment for a neurodegenerative disease

Page 48: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Guidance on diagnosis, management and

resources

Page 49: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

CADC dementia diagnosis toolkit

• Support diagnosis

• Multiple components

• Instructions

• Brief probe for

complaints

• Full assessment

• Differential diagnosis

• Questions and

interpretation

• Scripts

• Disclosure

• Driving

• Treatment

• Billing guidance

Page 50: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Conclusions

• FTLD includes a number of clinical syndromes–Linked by shared set of pathologies

• Diagnosis is primarily clinical–Support is available to facilitate

–Biomarkers available, more coming

• Genetic causes are common–Helping to understand entire course of illness

Page 51: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials

Adam Boxer

Brad Boeve

Howard Rosen

Brian Appleby

Yvette Bordelon

Bradford Dickerson

Kimiko Domoto-Reilly

Julie Fields

Jamie Fong

Ravlitza Gavrilova

Jill Goldman

Nupur Ghoshal

Neill Graff-Radford

Jon Graff-Radford

Ian Grant

Murray Grossman

Robin Hsiung

Edward Huey

David Irwin

David Jones

Daniel Kaufer

John Kornak

Joel Kramer

Walter Kremers

Walter Kukull

Maria Lapid

Irene Litvan

Diana Lucente

Ian Mackenzie

Mario Mendez

Bruce Miller

Chiadi Onyike

Alex Pantelyat

Len Petrucelli

Katherine Rankin

Rosa Rademakers

Katya Rascovsky

Julio Rojas

Erik Roberson

Carmela Tartaglia

Joanne Taylor

Sandra Weintraub

Biospecimens

Tatiana Foroud

Kelley Faber

Madeline Potter

Genotyping

Giovanni Coppola

Marisa Da Silva Ramos

Rosa Rademakers

Dan Geschwind

MRI

Kejal Kantarci

Denise Reyes

Kaely Thostenson

Image Sharing

Art Toga

Karen Crawford

Management:

Hilary Heuer

Leah Forsberg

Anna Karydas

Nellie Brushaber

Carmen Luk

Jeremy Sryjanen

The A/L/ALLFTD ConsortiumARTFL/LEFFTDS Investigators

Fellows

Kathryn Cousins

Peter Ljubenkov

Jaya Padmanabhan

Richard Tsai

Page 52: Frontotemporal lobar degenerationwai.wisc.edu/pdf/2019 Fall Update/Friday_Rosen_1 slide.pdfFrontotemporal lobar degeneration Clinical Approaches and Preparation for Clinical Trials